OPERAT I NG REV I EW CON T I NU E D The charts below show the results in the Angelman syndrome, Pitt Hopkins and Prader-Willi syndrome models. In the Angelman model, treatment also eliminated seizures in the knockout mice. EFFICACY IN MOUSE MODEL OF ANGELMAN WT-vehicle Ube3am- /p+ + vehicle WT+ NNZ2591 Ube3am-/p+ + NNZ2591 0 20 40 60 80 Distance travelled (cm) WT-vehicle Ube3am- /p+ + vehicle WT+ NNZ2591 Ube3am-/p+ + NNZ2591 0 2 4 6 Nest Building quality (grade 1 to 5) WT-vehicle Ube3am- /p+ + vehicle WT+ NNZ2591 Ube3am-/p+ + NNZ2591 0 5 10 15 20 Marble burying (n) WT-vehicle Ube3am- /p+ + vehicle WT+ NNZ2591 Ube3am-/p+ + NNZ2591 0 50 100 150 200 Time spent with the novel mouse (s) WT-vehicle Ube3am- /p+ + vehicle WT+ NNZ2591 Ube3am-/p+ + NNZ2591 0 20 40 60 80 Floating time (%) WT-vehicle Ube3am- /p+ + vehicle WT+ NNZ2591 Ube3am-/p+ + NNZ2591 0 2 4 6 8 Number of Platform crosses 7 Daily living Daily living Sociability Hypoactivity & anxiety Motor Cognition EFFICACY IN MOUSE MODEL OF PITT HOPKINS 8 WT + Vehicle Tcf4+/_ + Vehicle WT+ NNZ2591 Tcf4+/_ + NNZ2591 0.0 0.2 0.4 0.6 0.8 1.0 Force (N) WT + Vehicle Tcf4+/_ + Vehicle WT+ NNZ2591 Tcf4+/_ + NNZ2591 0 50 100 150 Time spent grooming (s) N_WT + Vehicle N_Tcf4+/_ + Vehicle N_WT+ NNZ2591 N_Tcf4+/_ + NNZ2591 0 20 40 60 Time spent with the novel mouse (s) WT + Vehicle Tcf4+/_ + Vehicle WT+ NNZ2591 Tcf4+/_ + NNZ2591 0 20 40 60 Freezing in % of 5min WT + Vehicle Tcf4+/_ + Vehicle WT+ NNZ2591 Tcf4+/_ + NNZ2591 0 2 4 6 Nest Building quality (grade 1 to 5) WT + Vehicle Tcf4+/_ + Vehicle WT+ NNZ2591 Tcf4+/_ + NNZ2591 0 50 100 150 Distance travelled Hypoactivity Daily living Motor performance Sociability Repetitive behavior Learning & Memory EFFICACY IN MOUSE MODEL OF PIT HOPKINS 8 WT + Vehicle Tcf4+/_ + Vehicle WT+ NNZ2591 Tcf4+/_ + NNZ2591 0.0 0.2 0.4 0.6 0.8 1.0 Force (N) WT + Vehicle Tcf4+/_ + Vehicle WT+ NNZ2591 Tcf4+/_ + NNZ2591 0 50 100 150 Time spent grooming (s) N_WT + Vehicle N_Tcf4+/_ + Vehicle N_WT+ NNZ2591 N_Tcf4+/_ + NNZ2591 0 20 40 60 Time spent with the novel mouse (s) WT + Vehicle Tcf4+/_ + Vehicle WT+ NNZ2591 Tcf4+/_ + NNZ2591 0 20 40 60 Freezing in % of 5min WT + Vehicle Tcf4+/_ + Vehicle WT+ NNZ2591 Tcf4+/_ + NNZ2591 0 2 4 6 Nest Building quality (grade 1 to 5) WT + Vehicle Tcf4+/_ + Vehicle WT+ NNZ2591 Tcf4+/_ + NNZ2591 0 50 100 150 Distance travelled Hypoactivity Daily iving Mot r performance Sociability Rep titive behavior Learni g & Memory Efficacy in mouse model of Angelman (Ube3a) Efficacy in mouse model of Pitt Hopkins (Tcf4) (cm) Neuren Pharmaceuticals Limited Annual Repor t 2022 10
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